Bridging the Gap: Conference Record [Abstract book, International Conference on AIDS (12th: 1998: Geneva, Switzerland)]

530 Abstracts 31174-31177

12th World AIDS Conference

Impaired proliferative responses to o-CD3 and/or to ConA were detected in 32
and 76% of HIV(+) children with CD4 > 500//pl and CD4 < 500//il respectively.
Defecient PHA responses were observed in 40% of HIV(+) with CD4 < 200/Il.
Responses to a-CD28 -CD2 and -CD69 were the most preserved during disease
progression.
Conclusions: HIV-1(+) children showed a CD8+ lymphocytosis being the
CD28-DR+ phenotype dominant. The progressive CD4+ lymphopaenia was not
selective for theCD4+CD28+ subpopulation. Impaired T cell proliferation with
anti-CD3 and ConA precedes the decline in CD4+ and CD8+CD28+ lymphocytes.
The in vitro conserved functional capacity of CD28 during disease progression
may reflect a down regulation of CD80 or other accessory molecules in APC.
31174 Partial immune restoration within 6 months of highly
active antiretroviral therapy
Laurence Weiss1, P. Ancuta2, A. Roux1, P.M. Girard3, M.D. Kazatchkine2,
N. Haeffner-Cavaillon2. 1 Hopital Broussais - Laboratoire D'lmmunologie
Biologique 96 Rue Didot - 75014 Paris; 2lnserm U430 - Hospital Broussais
Paris; 3Service Des Maladies Infectieuses - Hospital Rothschild, Paris, France
We have prospectively assessed phenotypic and fonctionnal parameters of immune restoration following initiation of highly active antiretroviral therapy (HAART).
Methods: Three-color flow cytometry for the assessment of T-cell subsets, V/I
TCR repertoires and cytokine production.
Results: 19 patients were enrolled. The mean CD4' cell count, at entry, was of
315 ~ 126/mm3. Baseline plasma HIV-RNA levels ranged between 3.9 and 5.6
log/mL. Under HAART, plasma HIV-RNA levels decreased below the threshold
of detection of 500 copies/mL in all patients. Absolute counts of CD3+CD41
T cells increased significantly from day 60 (P = 0.001). The increase in percentages of CD3+CD4+ cells only achieved significance after 6 months. Naive
CD45RA+CD62L+CD4+ cells increased from month 4 (P = 0.0008). Expression
of the activation markers (CD25 and HLA-DR on CD4+ cells and CD38 on CD8+
cells) decreased significantly. The percentage of CD8+ cells lacking the CD28
antigen decreased from month 4 (P = 0.003). There was no significant change
in V/ TCR usage in CD4+ and CD8+ T cells. Following stimulation with soluble
anti-CD3 mAb in vitro, overexpression of the CD69 antigen on CD4~ and CD8+
T cells that was observed prior to HAART was not seen any more from month 6.
Finally, there was no improvement in the ability of CD4+ T cells to produce IL-2
and interferon-y in vitro after 6 months of therapy.
Conclusions: Thus, after 6 months of HAART, we observed a significant increase in the number and percentage of CD3+CD4+T cells and in naive CD4+T
cells, as well as a significant decrease in the proportion of active circulating T
cells expressing activation markers. There was no significant change in V/ usage
by CD4+ and CD8+T cells. There was no significant improvement in the ability of
in vitro stimulated T cells to produce Thl cytokines. Data obtained after 9 months
of follow up will be presented.
31175 Depressed responses to mycobacterial antigens in HIV
patients receiving active antiretroviral therapy
Corinne Amiel1, J.P. Kusnierz1, Y. Mouton2, J.L. Stanford3, A. Capron1,
G.M. Bahr1. Institut Pasteur de Lille, INSERM U167, 1 Rue Du Prof. Calmette
59019 Lille; 2lnstitut Maladies Infectieuses, Tourcoing, France, 3University
College of London, London, England
Objectives: To determine whether patients on highly active antiretroviral therapy (HAART) and with low viral load present normal proliferative responses to
mycobacterial antigens.
Subjects and Methods: 15 HIV1-infected subjects (CDC-category A or B) who
had received HAART for at least 3 months were included in this study. All patients
presented very low (<1000 copies/ml) or undetectable viral load and had clinically
stable disease. Proliferative assays with sonicated mycobacterial antigens from 5
different species, heat-killed BCG and M. vaccae, as well as other recall antigens
including C. albicans and S. aureus were evaluated. A group of 26 seronegative
healthy volunteers was included and tested in parallel. A stimulation index >3
was considered as a positive response.
Results: All tested controls and 80% of HIV+ patients presented a positive
proliferative response to S. aureus. Responses to C. albicans were observed in
cultures from 84% of healthy controls and 88% of patients. In contrast, the %
of HIV patients presenting positive responses to various mycobacterial antigens
was significantly lower than that of seronegative controls. Maximum responses in
both groups was found to be directed to the sonicated antigen of M. tuberculosis;
however only 47% of patients, in contrast to 81% of healthy controls, showed
detectable responses. On the other hand, 74% of healthy controls were able to
respond to both the soluble and the heat-killed BCG antigens whereas only 24%
of patients showed similar ability to respond to both antigens.
Conclusion: A profound defect in the recognition of mycobacterial and recall
antigens in clinically stable HIV+ patients on HAART has been demonstrated.
These data argue in favor of a defective recognition of the protective common
mycobacterial antigens in HIV infection. This necessitates the consideration of

mycobacterial vaccines in the immunotherapeutic approaches against HIV infection.

31176 1 Alterations of CD45 isoforms expression in paediatric
HIV-1 infection predicts disease progression
Rafael Sirera1, F. Carbonell2, D. Perez-Tamarit3, M.C. Otero3,
M.A. Calvo-Bermudez3, F. Asensi3, A. Gonzalez-Molina1. 'Inmunologia-Centro
de Investigacion, Avda. de Campanar, 21 - Hospital la Fe (46009-Valencia);
2U?citometria de Flujo. Centro de Trasfusiones. Comunidad Valencia;
31nfecciosos-Hospital Infantil la Fe, Valencia, Spain
Background and Goal: The expression of CD45RA and CD45RO defines naive
and memory cells respectively and is reciprocally expressed on T lymphocytes.
Unprimed cells, after antigenic stimulation differentiate into CD45RO cells, which
play an important role in antigen-specific responses. The goal of this study was to
establish age-related differences in lymphocyte subpopulations and proliferative
responses to gain understanding of T cell activation in pediatric HIV disease and
to assess as surrogates for disease progression.
Material and Methods: Seroreverted children were controls (SR, n = 34).
HIV+ children (n = 35) were split into three categories attending to the age of
presenting severe CD4 lymphopenia (CD4 < 15%): a) Fast Progressors (FP, n =
6), before 2 years of age. b) Slow Progressors (SL, n = 24) at 7-10 years. c) Long
Term Non Progressors (LTNP, n = 5), asymptomatic, with normal CD4 cell counts
and older than 10 years old. Results were compared also by age. Three-color
flow cytometry was used to identify CD4 and CD8 lymphocytes as CD45RA
or CD45RO. PBL from each sample were stimulated with PHA, ConA, PWM y
a-CD3 and proliferative responses were determined by means of 3H-thymidine
incorporation.
Results: SR children showed a dominance of naive lymphocytes in CD4 and
CD8 populations. However in FP children was observed from birth a severe
CD4 lymphopenia mainly of CD45RA cells and a CD8 lymphocytosis mainly of
memory phenotype. SP showed balanced memory/naive populations and from
6-7 years of age (2 to 3 years before severe CD4 lymphopenia) changed their
profiles being similar to FP. Proliferative responses were impaired from birth in
FP and preceding severe CD4 lymphopenia in SP. LTNP showed CD4 counts like
controls and a slight increase of CD8CD45RO lymphocytes. Their proliferative
responses were like controls.
Conclusions: In HIV-1-infected patients there was a preferential depletion
of CD4CD45RA cells, which was most pronounced in the symptomatic phase.
There was a significant relative increase in the CD8CD45RO cell subset that
correlated strongly with the decline in total CD4 cells. The progressive severe
CD4D45RA lymphopenia and CD8CD45RO lymphocytosis can be used as a
prognostic marker of immune deterioration. This with functional studies can be
used to monitor disease progression and therapeutic benefits.
115*/31177 Improved cellular immunity in acute HIV-1 infection
following antiretroviral therapy
Julie McElrath1, U. Malhotra2, L. Musey2, M. Berry2, Y. Huang1, L. Corey2.
I Fred Hutchinson Cancer Research Center, 1100 Fairview Aven Seattle WA
98109; 2University of Washington, Seattle, USA
Objectives: The ultimate failure of CTL to control HIV-1 infected persons may
result from the inability of CD4+ T cells to provide help for these effector activities.
To deteringe if viral suppression can improve HIV-1-specific cellular immunity,
we prospectively examined T cell function in pationts with acute HIV-1 infection
receiving potent anti-HIV-1 therapy.
Methods: Eleven acutely infected patients received open-label ZDV, 3TC, and
indinavir over 200-300 days, and their immune responses were compared to
30 untreated pationts. Plasma HIV-1 RNA levels were determined by the bDNA
amplification method. In vitro lymphoproliferation (LP) was assessed to Candida,
Tetanus, HIV-1 p24 and gp160 abd reported as stimulation indices (SI). Precursor CTL frequencies were measured by antigen-specific stimulation in a limiting
dilution assay.
Results: In all patients, 4-12 weeks of potent anti-retroviral treatment resulted
in suppression of plasma HIV-1 RNA. Within 50 days, significant improvement
in LP responses (SI) were demonstrated to Candida (p = 0.04), Tetanus (p =
0.04) and HIV-1 p24 (p = 0.04) in the treated patients in comparison to their
pretreatment levels. When LP responses in the treated and untreated patients
were contrasted at the same time from infection, significant increases were found
in the treated patients (Candida, Tetanus, p24:P = 0.0001;gpl60:P = 0.01). The
response rate to HIV-1 p24 antigen rose to 67% by day 200 with a median SI to
1.6. There was an inverse correlation of p24 -specific SI with plasma HIV-1 RNA
levels. Analysis thus far of pCTL frequencies in 6 patients indicate a maintenance
of respenses to HIV-1 Env, Gag, and/or Pol over 200 days of treatment.
Conclusions: Potent anti-retroviral therapy initiated in acute HIV-1 infection
may salvage HIV-1-specific helper responses and improve memory responses to
antigens which the patients have been previously exposed. The treatment effect
may provide T cell help to maintain HIV-1 specific cytotoxic activities. These
findings provide optimism that amelioration of T helper dysfunction is feasible if
therapy is initiated early in infection.